Myxopyronins and corallopyronins are 2-pyrone-containing antibiotics which present a significant opportunity in antibacterial therapy. They constitute a synthetically accessible, unexploited series of low molecular weight bacterial RNA polymerase (RNAP) inhibitors with favorable properties: selectivity vs. human RNAP, cell penetration (minimal inhibitory concentrations (MICs) at concentrations comparable to in vitro bacterial RNAP IC.sub.50 s), and potency against rifampicin-resistant S. aureus equal to that against a rifampicin-susceptible strain.
Corallopyronin A/B and myxopyronin A/B are natural products isolated from gliding bacteria (Corallococcus coralloides; Myxococcus fulvus) and discovered to be RNAP inhibitors. Reichenbach, H., Hofle, G., Irschik, H., Kohl, W., Liebigs Ann. Chem., 1983, 1656; Reichenbach, H., Hofle, G., Irschik, H., Kohl, W., Liebigs Ann. Chem., 1984, 1088;
Reichenbach, H., Hofle, G., Irschik, H., Jansen, R., Liebigs Ann. Chem., 1985, 822. The structures of these compounds are closely related having in common a 3-acyl-4-hydroxy-2-pyrone with an alkyl chain at the 6-position bearing a vinyl carbamate functionality, a feature atypical of natural products. They differ only in the substitution on the alkyl chain attached to the 3-position of the pyrone, the corallopyronins being more elaborate (FIG. 1(a)). The pyronins have good intrinsic activity in antibacterial assays against both E. coli and S. aureus RNA polymerase. This activity is specific with respect to human or SP6 polymerases. MIC data (see Table I) show that these compounds, like rifampicin, are not absorbed well by E. coli but that they have intrinsic activity against both gram positive and gram negative bacteria.
TABLE I In Vitro IC.sub.50 (.mu.M) MIC (.mu.m/ml) E. coli S. aureus Human SP6 E. coli E. coli Compound RNAP RNAP RNAP RNAP Rev/RRE S. aureus MCR BAS Myxopyronin A/B 10 10 &gt;200 &gt;200 100 4 180 1.6 Corallopyronin A/B 6 10 &gt;200 &gt;200 100 4 &gt;200 0.4
An attractive feature of this series of compounds is their activity against strains resistant to rifampicin. The MIC for rifampicin is ca. 10 nM against susceptible strains, but falls off against resistant strains (MIC&gt;10 .mu.M). The use of rifampicin is limited by the development of bacterial resistance. Both myxo- and corallopyronins are equiactive against Rif-susceptible and Rif-resistant S. aureus.
Pyrones have been used in the prior art to elicit a biological effect in a few instances, but in none of these instances have they been used as an antibacterial agent. 2H-Pyran-2,6(3H)-dione derivatives are reported to be active at reasonable doses in a passive cutaneous anaphylaxis model in rats when administered by either the intravenous or oral route. Snader, K. M. et al., J. Med. Chem., 1979, 22, 706; Chahrin, L. W., Snader, K. M., Williams, C. R., 2H-Pyran-2,6(3H)-dionederivate. German Patent 25 33 843. In a second case, simple 3-(1-oxoalkyl)-4-hydroxy-6-alkyl-2-pyrones were found to be effective in vitro in the inhibition of human sputum elastase. Cook, L., Ternai, B., Ghosh, P., J. Med. Chem., 1987, 30, 1017. Lastly, a series of pyrone derivatives were found to be effective inhibitors of HIV protease in both enzymatic assays and cell culture (FIG. 1(b)). Skulnick, H. I., et al., J. Med. Chem., 1995, 38, 4968. No synthetic investigations or medicinal uses of pyronin antibacterials have been reported in the literature.
The present invention provides novel intermediates useful in the synthesis of myxopyronin A and derivatives thereof. In addition, the present invention provides processes for synthesizing myxopyronin A and derivatives thereof as well as corallopyronins.